1. Field of the Invention
This invention concerns derivatives of carbostyril as agents in the treatment of diseases characterized by an overproduction of thromboxane or an imbalance of thromboxane/prostacyclin, by inhibiting both thromboxane synthetase and cyclic-AMP phosphodiesterase.
2. Related Disclosures
Research work has established that in many tissues the major product of arachidonic acid metabolism by the cyclooxygenase enzyme system is either of two unstable substances, thromboxane A.sub.2 (TxA.sub.2) or prostacyclin (PGI.sub.2). The discovery of TxA.sub.2 and PGI.sub.2 has significantly increased our understanding of vascular homeostasis. PGI.sub.2 for instance is a powerful vasodilator and inhibitor of platelet aggregation, and in this last respect is the most potent endogenous substance so far discovered. The PGI.sub.2 synthetase enzyme is located in the endothelial layer of the vasculature, and while it has its own cyclooxygenase system it can utilize endoperoxides released by blood platelets when thromboxane synthetase is inhibited.
TxA.sub.2 is synthesized by the thromboxane synthetase enzyme which is located in, for example, the blood platelets. It is a powerful vasoconstrictor and pro-aggregatory substance, the direct opposite functions to those of PGI.sub.2. A balance in favor of PGI.sub.2 is regarded as beneficial in many conditions such as thrombosis, atherosclerosis, vasospastic cardiovascular disease, diabetes, renal disorders, inflammation, endotoxic shock and possibly even tumor metastasis.
The foregoing demonstrates the desirability of altering the prostacyclin/thromboxane ratio in favor of the former. One method of attempting to achieve this goal is to take advantage of the fact that the immediate precursor to both PGI.sub.2 and TxA.sub.2 is the same substance, the unstable endoperoxide PGH.sub.2. If the synthesis of TxA.sub.2 can be blocked, it is then reasonable to expect that more PGH.sub.2 will be available for conversion to PGI.sub.2. This activity has been demonstrated by several compounds, e.g., dazoxiben, but the levels of prostacyclin thus produced are quite low and may not be therapeutically useful.
Prostacyclin exerts its anti-aggregatory action by elevating cyclic adenosine monophosphate (cyclic-AMP) levels. It is known that cyclic-AMP phosphodiesterase inhibitors, which retard the degradation of cyclic-AMP to the inactive AMP, act synergistically with prostacyclin in elevating cyclic-AMP levels. Thus it is clear that the ability to both inhibit thromboxane synthesis and to inhibit cyclic-AMP phosphodiesterase activity greatly increases the anti-aggregatory potential of a compound. Although both thromboxane inhibitors and cyclic-AMP phosphodiesterase inhibitors are known, the combination of both activities in one compound is novel.
Other carbostyril compounds are described in U.S. Pat. Nos. 3,962,445; 4,309,432; 4,442,106; 4,482,560; 4,487,772; 4,530,930; in Japanese Patent Nos. J5 5076872; J5-1118772; J5 7159778; and in EP No. 148623. The disclosed compounds are described as having antimicrobial, anti-histaminic, antihypertensive, anti-arhythmic, and cardiotonic activities, to be useful in treating glaucoma and to be inhibitors of blood platelet agglutination and antigen-antibody reactions.